A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression

Erica M. Richards, Daniel C. Mathews, David A. Luckenbaugh, Dawn F. Ionescu, Rodrigo Machado-Vieira, Mark J. Niciu, Wallace C. Duncan, Neal M. Nolan, Jose A. Franco-Chaves, Thomas Hudzik, Carla Maciag, Shuang Li, Alan Cross, Mark A. Smith, Carlos A. Zarate

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Rationale: Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. Objective: This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. Methods: We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). Results: Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders. Conclusion: These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

Original languageEnglish (US)
Pages (from-to)1119-1130
Number of pages12
Issue number6
StatePublished - Mar 1 2016
Externally publishedYes


  • AZD2327
  • Anxiety
  • Anxiolytic
  • Anxious depression
  • BDNF
  • Biomarkers
  • EEG
  • Major depressive disorder
  • Opiate
  • Preclinical

ASJC Scopus subject areas

  • Pharmacology


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